Introduction A proportion of patients preferentially methylate thiopurines, resulting in high levels of methylated metabolites and low levels of thioguanine nucleotides. This can result in hepatotoxicity and treatment non-response. Co-prescription of thiopurines (at 25%–50% of standard dose) with allopurinol, (which blocks xanthine oxidase) circumvents this problem, optimising metabolite profile and clinical outcome and additionally overcomes atypical side effects experienced on thiopurine monotherapy. Using data from a large cohort of patients receiving combination therapy, we aimed to establish what proportion of all patients starting thiopurines could benefit from combination treatment.
Methods Using data from a cohort of 109 patients recruited retrospectively, all receiving combination therapy in our clinic, 1yr clinical response rates were calculated by indication. Using data from a published prospective cohort and side effect rates from meta-analysis, we calculated the proportion of all patients starting thiopurines that could be salvaged from treatment failure to 1yr remission by combination therapy.
Results 10/17 (59%) of hyper-methylating non-responders to thiopurine monotherapy, 8/17 (47%) of those treated for atypical side effects and 11/15 (73%) switched for hepatotoxicity achieved remission at 1 year. Using these response rates, potential gain was calculated from a prospective cohort (n=207) from our centre. 60 patients discontinued thiopurine monotherapy due to non-specific side effects, eight due to hepatitis and 32 were hyper-methylating non-responders, a total of 100 patients with clear indications for combination treatment. Our results predict that 53/100 could have achieved 1-year remission, representing 26% of the original cohort. Using a more conservative published side effect rate of 10% (Prefontaine et al 2010, Cochrane Database of Systematic Reviews, CD000545) and excluding 2.8% due to side effects unsuitable for combination therapy (pancreatitis and myelotoxicity), 12% of all patients started on azathioprine could have their outcome on thiopurine therapy converted from treatment failure to 1-year remission by combination therapy.
Conclusion 12%–26% represents the “missed opportunity” of patients starting thiopurine monotherapy which can be realistically overcome by combination treatment with allopurinol, converting treatment failure to successful 1-year remission. Given that thiopurines remain a key part of most IBD treatment paradigms, this is an important opportunity for improved treatment outcomes in IBD.
Competing interests None declared.